Mitochondrial DNA copy number variation in asthma risk, severity, and exacerbations - 24/09/24

Doi : 10.1016/j.jaci.2024.08.022

Weiling Xu, MD ^a, Yun Soo Hong, MD, PhD ^b, Bo Hu, PhD ^c, Suzy A.A. Comhair, PhD ^a, Allison J. Janocha, BS ^a, Joe G. Zein, MD, PhD ^d, Ruoying Chen, PhD ^c, Deborah A. Meyers, PhD ^d, David T. Mauger, PhD ^e, Victor E. Ortega, MD, PhD ^d, Eugene R. Bleecker, MD ^d, Mario Castro, MD ^f, Loren C. Denlinger, MD, PhD ^g, John V. Fahy, MD ^h, Elliot Israel, MD ⁱ, Bruce D. Levy, MD ⁱ, Nizar N. Jarjour, MD ^j, Wendy C. Moore, MD ^k, Sally E. Wenzel, MD ^l, Benjamin Gaston, MD ^m, Chunyu Liu, PhD ⁿ, Dan E. Arking, PhD ^b, Serpil C. Erzurum, MD ^a,^o,^⁎
for the
National Heart, Lung, and Blood Institute (NHLBI) Severe Asthma Research Program and TOPMed mtDNA Working Group in NHLBI Trans-omics for Precision Medicine (TOPMed) Consortium
^a Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
^b Department of Genetic Medicine, McKusick-Nathans Institute, Johns Hopkins University School of Medicine, Baltimore, Md
^c Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
^d Department of Internal Medicine, Division of Respiratory Medicine, Mayo Clinic, Scottsdale, Ariz
^e Department of Public Health Sciences, Pennsylvania State University School of Medicine, Hershey, Pa
^f Department of Medicine, University of Kansas School of Medicine, Kansas City, Kan
^g Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin, Madison, Wis
^h Department of Medicine, San Francisco School of Medicine, University of California, San Francisco, Calif
ⁱ Department of Medicine, Harvard Medical School, Boston, Mass
^j Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wis
^k Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC
^l Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh School of Medicine, Pittsburgh, Pa
^m Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Ind
ⁿ Department of Biostatistics, School of Public Health, Boston University, Boston, Mass
^o Integrated Hospital Care Institute, Cleveland Clinic, Cleveland, Ohio

^∗Corresponding author: Serpil C. Erzurum, MD, Cleveland Clinic, 9500 Euclid Ave, NB2, Cleveland, OH 44195.Cleveland Clinic9500 Euclid AveNB2ClevelandOH44195

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Tuesday 24 September 2024

Graphical abstract

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Abstract

Background

Asthma pathophysiology is associated with mitochondrial dysfunction. Mitochondrial DNA copy number (mtDNA-CN) has been used as a proxy of mitochondrial function, with lower levels indicating mitochondrial dysfunction in population studies of cardiovascular diseases and cancers.

Objectives

We investigated whether lower levels of mtDNA-CN are associated with asthma diagnosis, severity, and exacerbations.

Methods

mtDNA-CN is evaluated in blood from 2 cohorts: UK Biobank (UKB) (asthma, n = 39,147; no asthma, n = 302,302) and Severe Asthma Research Program (SARP) (asthma, n = 1283; nonsevere asthma, n = 703).

Results

Individuals with asthma have lower mtDNA-CN compared to individuals without asthma in UKB (beta, −0.006 [95% confidence interval, −0.008 to −0.003], P = 6.23 × 10⁻⁶). Lower mtDNA-CN is associated with asthma prevalence, but not severity in UKB or SARP. mtDNA-CN declines with age but is lower in individuals with asthma than in individuals without asthma at all ages. In a 1-year longitudinal study in SARP, mtDNA-CN was associated with risk of exacerbation; those with highest mtDNA-CN had the lowest risk of exacerbation (odds ratio 0.333 [95% confidence interval, 0.173 to 0.542], P = .001). Biomarkers of inflammation and oxidative stress are higher in individuals with asthma than without asthma, but the lower mtDNA-CN in asthma is independent of general inflammation or oxidative stress. Mendelian randomization studies suggest a potential causal relationship between asthma-associated genetic variants and mtDNA-CN.

Conclusion

mtDNA-CN is lower in asthma than in no asthma and is associated with exacerbations. Low mtDNA-CN in asthma is not mediated through inflammation but is associated with a genetic predisposition to asthma.

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Key words : Mitochondrial DNA, asthma, exacerbations

Abbreviations used : ATS, BMI, CI, CRP, Feno, GPx, GWAS, IV, MR, mtDNA, mtDNA-CN, PD, SARP, SD, SNP, SOD, TOPMed, UKB, WBC, WGS